Free radicals, or more specifically, reactive oxygen species (ROS), have been proposed as critical mediators of dysfunction and disease for a large number of disorders, including many in the brain related to Alzheimer's disease, accelerated aging, other neurodegenerative diseases, severe mental illnesses and vascular disease. However, there are simply no methods of assessing ROS levels in human tissue. We believe this has created an unmet need for an imaging approach that could quantify and monitor levels of mitochondrial and inflammatory ROS in brain. We have therefore developed a set of novel positron emission tomography (PET) tracers that allow direct assessment of ROS based on their behavior and similarity to dihydroethidine (DHE), an optical probe that is well validated for imaging ROS in animals. Based on recently acquired, highly encouraging data, we believe that, as detailed in the Specific Aims and Research Plan sections, these tracers will translate to direct applications in human brain imaging. Furthermore, we believe that a major application will be in improving our understanding of Alzheimer's disease pathology and providing assistance in designing appropriate disease-modifying treatments. PUBLIC HEALTH RELEVANCE: This proposal intends to develop a method for using a PET scanner to image oxygen-based free radical levels in the human brain. Free radicals are small molecules in the body that are extremely reactive and when elevated they may injure the body by altering proteins and other important chemicals. As free radicals may be involved in many diseases, including Alzheimer's disease, a method to allow scientists and clinical investigators a way to monitor levels of free radicals should greatly increase our understanding of how injury to the brain occurs in these diseases, and how treatments for these disorders could be developed faster.